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Francisco Rodríguez became the youngest pitcher ever to reach 100 saves, when he did so on September 10, 2006, at age 24 years and 264 days. He then set the all-time single-season mark for saves in 2008.

He was pitching already at the age of seven at the Graciano Ravelo Baseball School, and was signed as an undrafted free agent by the Anaheim Angels in 1998. He pitched for Venezuela at the 1998 Pan-American Youth Championship in Mexico.

In the minors, Rodríguez pitched at rookie league-level Butte in 1999, primarily as a starter, with an ERA of 3.31 and a record of 1-1 before starting one game at low-A Boise. In 2000, he was in Lake Elsinore of the California League as a starter, posting a record of 4-4 with a 2.81 ERA. In 2001, he stayed in the California League, with the Rancho Cucamonga Quakes, where he posted an ERA of 5.38 as a starter.

In spite of that, Rodríguez moved up to Double A and to Triple A during the 2002 season, when he was 20 years old, and even had a few games at the major league level that year. He became a reliever, starting no games at any level from 2002 through now. His ERA at Arkansas in the Texas League was 1.96 as he had 9 saves and a 3-3 record. In Triple A at Salt Lake in the PCL, he had an ERA of 2.57 with a record of 2-3 and 6 saves.

In the majors in 2002, Rodríguez came up for 5 games, pitching 5 2/3 innings, without giving up a run. He was the youngest player in the league. He burst on to the national scene with a highly successful postseason run that saw him win five games while striking out 28 batters in 17 2/3 innings, earning him the nickname of "K-Rod". Controversially, he was included on the postseason roster over Aaron Sele, who had been injured much of the year; his inclusion was made possible by an ambiguity in the postseason roster rules that allowed for an injury replacement for any player on the 40-man roster: Rodriguez replaced Steve Green, who had been on the disabled list the entire year.

In 2003, in the majors, Rodríguez was mainly used as a set-up man for Troy Percival. He appeared in 59 games (all in relief) at the age of 21, finishing 23 but getting only 2 saves. His ERA was 3.03, and he had a record of 8-3. In 2004, he began to get saves, with 12 in 69 games, posting an ERA of 1.82. He was named to the All-Star team.

In 2005 Rodríguez recorded 45 saves to lead the league, and in 2006 his league-leading 47 put him on the way to winning the Rolaids Relief Award. He had another good season in 2007, going 5-2, 2.41 with 40 saves as the Angels won their division. In 2008, he began to rack up saves at an unseen rate, as the Angels were winning a lot of close games. He was already closing in on 40 saves by the All-Star Game, to which he was selected, and he set a new major league mark when he notched his 58th save of the season against the Seattle Mariners on September 13. This shattered the record of 57 held by Bobby Thigpen since 1990. He ended the season with 62, along with a 2.24 ERA, and earned a second Rolaids Relief Award. However, he was shaky during the postseason, losing Game 2 of the ALDS to the Boston Red Sox in the 9th inning .

Following his record-setting season, Rodríguez signed a 3-year, $37-million deal with the New York Mets. After a so-so season in 2009 in which he went 3-6, 3.71 with 35 saves, he ran into trouble off the field in mid-2010, when he punched the father of his girlfriend in the face several times in front of witnesses at Citi Field, following a Mets loss to the Colorado Rockies on August 11. He was arrested, detained overnight, charged with third-degree assault and placed on the restricted list by the Mets. He returned to action three days later after issuing a brief apology, but on August 16 the team announced that Rodríguez had torn a ligament in his thumb during the altercation, ending his season. For the year, he went 4-2, 2.20 with 25 saves in 53 games and 67 strikeouts in 57.1 innings of work. The next day, the Mets announced that Rodríguez had been placed on the disqualified list and that he would not be paid until able to pitch again. There was also speculation that may try to void the last year of his contract, worth $11.5 million. The Major League Baseball Players Association immediately announced that it was filing a grievance against the team's action, calling the decision to cut Rodríguez's salary and to void his garanteed contract as "without basis". On December 3, Rodríguez pleaded guilty to attempted assault and was sentenced to take anger management classes to avoid jail time; he also pleaded guilty to disorderly conduct charges for harassing his girlfriend, but he still faced a civil lawsuit from his victim for the injuries he suffered.

After the Mets quietly dropped their attempt to cut him during the off-season, a contrite Rodriguez showed up in spring training in February 2011, expressing regret and remorse for his actions the previous year. He was back in the closer's role and pitched fairly well over the season's first half, going 2-2 with 23 saves and 3.16 ERA. But with the Mets unlikely to mount a serious challenge for a playoff spot, the team faced a dilemma: Rodriguez already had 34 games finished by the All-Star break, and his contract included a vesting option worth $17.5 million if he reached a total of 55 this season. Not wanting to back themselves into such a huge financial commitment, the Mets traded him to the Milwaukee Brewers on July 12th in return for two players to be named later. In Milwaukee, he was to become the set-up man for closer John Axford, a move which would prevent the troublesome option from vesting. Indeed, he pitched 31 games for the Brewers down the stretch, without recording a single save and only 2 games finished. That said, he gave the Brew Crew everything they were looking for, going 4-0 with a 1.86 ERA and 33 Ks over 29 innings during that time. He then pitched two scoreless innings in the NLDS against the Arizona Diamondbacks and then gave up a run in three innings as Milwaukee lost to the St. Louis Cardinals in the NLCS.

After the season, Rodriguez was a free agent, as his option had failed to vest, but he found that demand for his services was very low. As a result, he decided to re-sign with Milwaukee for a year, but it soon came out that he was far from happy with the turn of events. In late February of 2012, stories indicated that he was suing his former agents, Paul Kinzer and Arn Tellem, for failing to file a list of teams to which he would not accept a trade at the time of signing his contract with the Mets. The Brewers should have been on that list, but were not, making the trade that made him lose out on his vesting option possible. He had already fired the two agents the previous July when he found out about the oversight, and had replaced them with Scott Boras, but he was now claiming professional malpractice, as, in his view, the trade that should never have been possible, and the consequent change in his usage pattern, had cost him a shot at a much more lucrative contract for future years. He settled the suit after the season for more than $2 million, while Kinzer was terminated for cause, indicating that there was something to his claim even though both parties agreed not to give further details as part of the out-of-court settlement. He managed to pitch fairly well in the first half of the season, serving as the set-up man for Axford, who began to struggle in June. On July 17th, manager Ron Roenicke announced that Rodriguez would be given the closer's role, with Axford relegated to less pressure-packed situations. Rodriguez was 2-4, 3.67 with 1 save and 39 Ks in 41 2/3 innings when the change was made. In his first game as closer on July 18th, he made things interesting, giving up a run, putting the tying run on 3rd base with none out and leaving the bases full in closing out a 4-3 win over the Cardinals; ironically, the win went to Axford, who had entered the game in the 5th to become the pitcher of record. Rodriguez finished the season with a disappointing record of 2-7, 4.38 and only 3 saves in 78 outings, as Axford quickly regained the closer's job. Francisco did strike out 72 in as many innings pitched, however. He ran into more legal trouble late in the season, facing misdemeanor assault charges for allegedly striking his wife during a domestic dispute on September 18th.

Rodriguez was back with the Brewers in [2013 Brewers|2013]] after missing the first six weeks of the season, although by then he had fallen down one more rank on the team's bullpen depth chart, with Jim Henderson also moving ahead of him. The season was a struggle for the Brewers, who were never in the race in the NL Central, although Rodriguez did get a chance to pitch in some high-leverage situations as Henderson and Axford both struggled with health and consistency issues. His record stood at 1-1, but with a sparkling 1.09 ERA and 10 saves in 25 appearances when he was traded to the Baltimore Orioles on July 23rd, with Milwaukee acquiring infield prospect Nick Delmonico in return. He was 2-1 with a 4.50 ERA in 23 games for the Orioles and did not pick up any saves as Jim Johnson was the team's closer.

In a surprising move, Rodriguez signed back with the Brewers for one year as spring training was getting under way on February 7, 2014. However, he was a victim of political circumstances, as a wave of violent protests in his native Venezuela forced him to delay his departure for Arizona. He finally managed to obtain a work visa and report to the Brewers with his girlfriend and two children on March 1st. He then suffered another delay because of a more unusual cause, as he injured his foot when he stepped on a cactus on the day before he was to make his first appearance in a Cactus League game (of course); the injury was described by manager Ron Roenicke as very painful, but not a cause for longer-term concern. In spite of all that, he started the year red hot, as did the Brewers. On April 26th, he registered his 11th save of the season, the most ever by a Brewers pitcher in April. He ended up with 44 saves to go along with a 5-5 record and a 3.04 ERA and made it back to the All-Star Game for the first time since 2009. However, the Brewers collapsed in the second half and missed the postseason. In 2015, he was one of the few bright lights on an underperforming Brewers team as he went 1-3, 2.21 and added another 38 saves as he once again was named to the All-Star team. There was speculation all season that he would be traded, but he stayed in Milwaukee the whole year. The anticipated trade came on November 18th, when he was sent to the Detroit Tigers for minor league IF Javier Betancourt and a player to be named.

On May 24, 2016, Francisco earned the 400th save of his career in a 3-1 win over the Philadelphia Phillies. It came at a time he was pitching very well for his new team, having converted 14 straight save opportunities after being charged with a blown save on opening day. He was only the sixth pitcher in major league history to reach the 400-save mark and was the active leader in the category.

By the age of 26, Rodríguez had pitched in post-season play five times already, in 2002, 2004, 2005, 2007 and 2008. In the 2002 World Series, which the Angels won, he pitched 8 2/3 innings in relief, getting 13 strikeouts with a 2.08 ERA. He had no saves, but a record of 1-1. He was welcomed back in Venezuela as a national hero after the Series, since he was front-page news there during the post-season.

Rodríguez has also pitched in the Venezuelan League, and was named to the League's All Star team as relief pitcher in 2004 and 2005.